Pediatric Research

BackgroundIntermittent hypoxemia (IH) is common in preterm infants and linked to brain injury. S100B is a glial-derived protein that rises early after neural injury and can be measured noninvasively in urine. We evaluated the relationship between IH burden and urinary S100B in preterm infants [&le;]32 weeks gestation. MethodsPreterm infants [&le;]32 weeks gestation were prospectively enrolled. Oxygen saturation was continuously monitored, and IH profiles were quantified using validated algorithms. Urine S100B was measured by ultrasensitive immunoassay. Infants with severe intraventricular hemorrhage were excluded. Spearman correlations examined associations between IH metrics and urinary S100B, overall and by gestational age subgroups. ResultsTwenty-one infants contributed 53 urine samples. Higher urinary S100B correlated with greater IH frequency, percent time in hypoxemia, longer event duration, and lower nadir saturations (all p <0.05). Short events showed the strongest correlations for frequency ({rho} = 0.50) and percent time ({rho} = 0.54), while longer events correlated most strongly with nadir ({rho} = -0.66). Extremely preterm infants demonstrated stronger associations for nadir and duration; very preterm infants only for percent time. S100B increased stepwise across IH burden tertiles. ConclusionsUrinary S100B increases with IH burden, with patterns varying by gestational age and event duration. Urinary S100B may provide an early, noninvasive biomarker of IH-related brain injury in preterm infants.

BACKGROUNDExtremely premature infants are treated with acetaminophen (APAP) for discomfort and patent ductus arteriosus. A recent study found an association between APAP metabolite levels in mothers breast milk and the diagnoses of both bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) in their infants. METHODSUrine samples from 314 infants <29 weeks gestation in the TOLSURF and PROP studies were analyzed by untargeted UHPLC:MS/MS. We performed multivariate logistic regression and meta-analysis to examine associations between APAP metabolite levels and clinical outcomes. RESULTS4-APAP sulfate was the highest detected and most abundant metabolite of 8 detected and was present in 98% of urines. In longitudinal studies (day 6-56), periods of elevated urinary 4-APAP-sulfate occurred in 24 of 28 infants and were of longer duration (10.1 vs 4.2 days, p=0.004) and higher levels (13.3 vs 5.6, p=0.013) in infants on enteral vs total parenteral nutrition. At both day 10 and 28 there were no significant associations between levels of APAP metabolites and BPD or ROP in all infants or only those on TPN or enteral feeds. CONCLUSIONIn two cohorts of premature infants, APAP metabolites were detected uniformly and levels were not associated with increased risk for two adverse clinical outcomes. Impact StatementO_LIPremature infants are treated with acetaminophen (APAP) for analgesia and closure of patent ductus arteriosus, however an association has been reported between APAP levels in maternal milk and infant bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). C_LIO_LIIn an untargeted metabolomic study of 2 cohorts of premature infants, the major urinary APAP metabolite was detected in most urine samples of all infants, and there were intervals of elevated levels. C_LIO_LIUsing both longitudinal and cross-sectional analyses, we found no association between APAP levels and either BPD or ROP. C_LIO_LIAlthough APAP is known to have toxic effects at high doses, our findings suggest that APAP exposure, at doses experienced by infants in these cohorts, does not increase the risk for two adverse outcomes in the neonatal period. C_LI

Abnormal respiratory microbiomes are reported in children with artificial airways, yet the timing and persistence of these disruptions have not been defined in infants following new tracheostomy placement. We conducted a prospective longitudinal study to characterize airway microbiome dynamics following new tracheostomy placement during early life, a critical period for microbiome development. Fifteen hospitalized infants <=12 months contributed 84 tracheal aspirate samples collected from day 1 through 3 to 4 months post-procedure. 16S rRNA sequencing revealed immediate and sustained community shifts. Staphylococcus abundance increased after tracheostomy, peaking at 40 days (mean 27%) before declining, with a more pronounced bloom in infants without home mechanical ventilation (HMV). Alpha diversity decreased significantly in the first 30 days (p<0.05) and returned to baseline by 61 to 90 days. Beta diversity analysis demonstrated marked compositional changes immediately post-tracheostomy and ongoing divergence through 3 to 4 months. Time since tracheostomy and clinical factors (gestational age, HMV, neurologic impairment) were significantly associated with microbiome structure (p=0.001). These findings provide novel evidence that tracheostomy induces rapid and prolonged airway microbiome disruption in infants, highlighting a previously uncharacterized window of vulnerability with implications for respiratory health and individualized care.

RationaleBronchopulmonary dysplasia (BPD) is the most common morbidity affecting very preterm infants. Gut fungal and bacterial microbial communities contribute to multiple lung diseases and may influence BPD pathogenesis. MethodsWe performed a prospective, observational cohort study comparing the multikingdom fecal microbiota of 144 preterm infants with or without moderate to severe BPD by sequencing the bacterial 16S and fungal ITS2 ribosomal RNA gene. To address the potential causative relationship between gut dysbiosis and BPD, we used fecal microbiota transplant in an antibiotic-pseudohumanized mouse model. Comparisons were made using RNA sequencing, confocal microscopy, lung morphometry, and oscillometry. ResultsWe analyzed 102 fecal microbiome samples collected during the second week of life. Infants who later developed BPD showed an obvious fungal dysbiosis as compared to infants without BPD (NoBPD, p = 0.0398, permutational multivariate ANOVA). Instead of fungal communities dominated by Candida and Saccharomyces, the microbiota of infants who developed BPD were characterized by a greater diversity of rarer fungi in less interconnected community architectures. On successful colonization, the gut microbiota from infants with BPD augmented lung injury in the offspring of recipient animals. We identified alterations in the murine intestinal microbiome and transcriptome associated with augmented lung injury. ConclusionsThe gut fungal microbiome of infants who will develop BPD is dysbiotic and may contribute to disease pathogenesis.Conclusions: The gut fungal microbiome of infants who will develop BPD is dysbiotic and may contribute to disease pathogenesis.

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a cause of neonatal hypoxic respiratory failure due to the failed transition of the pulmonary vasculature after birth. Mechanisms of disease are unknown, but we hypothesize they are directly related to insults in the intrauterine environment. The objective was to describe and compare placentas of PPHN infants to understand significant preceding factors from the maternal-fetal environment. MethodsWe conducted a case-control study of mother-infant dyads [&ge;]35 weeks gestation who delivered at a tertiary care center between 2020-2025. Cases were infants diagnosed with PPHN and treated with inhaled nitric oxide; controls were infants without congenital anomalies. Placentas underwent blinded histopathologic review using standardized criteria. Results106 placentas were analyzed (53 PPHN, 53 controls). Placental lesions were significantly more common in PPHN, including maternal vascular malperfusion (30.2% vs 9.4%, p<0.01), fetal vascular malperfusion (34.0% vs 17.0%, p=0.05), placental inflammation (66.0% vs 37.7%, p<0.01), meconium (43.4% vs 15.2%, p<0.01), and chorangiosis (7.6% vs 0%, p=0.04). ConclusionPPHN placentas demonstrate lesions of malperfusion, inflammation, and chronic meconium exposure, suggesting a complex interplay between intrauterine hypoxia and inflammation as a mechanism for the abnormal pulmonary vascular reactivity see in PPHN.

RationalePulmonary hypertension associated with bronchopulmonary dysplasia is a severe complication of preterm birth resulting in high mortality of up to 50% within the first 2 years of life. There is a direct relationship between bronchopulmonary dysplasia severity and incidence of associated pulmonary hypertension. However, it is challenging to clinically characterize severe bronchopulmonary dysplasia with and without pulmonary hypertension and there is need for better understanding of the two entities. ObjectivesTo identify markers to help understand biological processes and endotype characterization of infants with pulmonary hypertension associated with bronchopulmonary dysplasia in tracheal aspirates. MethodsWe conducted multi-omic analysis of tracheal aspirates via miRNA PCR arrays, RNA sequencing and mass spectrometry proteomics in preterm infants with severe bronchopulmonary dysplasia with (n=21) and without (n=25) pulmonary hypertension. ResultsOur study analysis revealed 12 miRNAs (hsa-miR-29a, has-miR-542-3p, has-miR-624, has-miR-183, hsa-miR-501-3p, hsa-miR-101, hsa-miR-3131, hsa-miR-3683, hsa-miR-3193, hsa-miR-3672, hsa-miR-3128, and hsa-miR-1287); 6 transcripts (IL6, RPL35P5, HSD3B7, RNA5SP215, OR2A1-AS1, and RNVU1-19), and 5 proteins (CAPS, AAT, KRT5, SFTPB, and LGALS3BP) with significant differential expression in preterm infants with severe lung disease with pulmonary hypertension when compared to infants with severe lung disease but no pulmonary hypertension. Pathway analysis of the integrated multi-omic expression signatures revealed NFkB, VEGF, SERPINA1, IL6 and ERK12 as target molecules for miRNAs, and angiogenesis and hyperoxia stress as recurrent pathways of individual markers. ConclusionOur multi-omic analysis of tracheal aspirates revealed a comprehensive thumbprint of miRNAs, mRNAs and proteins that could help endotype infants with severe lung disease and pulmonary hypertension.

ObjectivesNecrotizing enterocolitis (NEC) is a life-threatening disease, and the most common gastrointestinal emergency in premature infants. Accurate early diagnosis is challenging. Modified Bells staging is routinely used to guide diagnosis, but early diagnostic signs are non-specific, potentially leading to unobserved disease progression, which is problematic given the often rapid deterioration observed in NEC infants. New techniques, using biomarkers as diagnostic tool to improve diagnosis of NEC, are emerging. Here we investigated faecal cytokine levels, coupled with gut microbiota profiles, as a non-invasive method to discover specific NEC-associated signatures that can be applied as potential diagnostic markers. Study designPremature babies born below 32 weeks of gestation were admitted to the 2-site neonatal intensive care unit (NICU) of Imperial College hospitals (St. Marys or Queen Charlottes & Chelsea) between January 2011 and December 2012. All but two babies received a first course of antibiotics from birth onwards. Faecal samples from diapers were collected consecutively during the NICU stay. ResultsEvaluation of microbiota profiles between the study groups revealed only minor differences. However, at later time points, significant changes in microbiota structure were observed for Firmicutes, with Enterococcus being the least abundant in Bell stage 2/3 NEC. Faecal cytokine levels were similar to those found in previous studies evaluating systemic cytokine concentrations in NEC settings, but measurement in faeces represents a non-invasive method to evaluate the early onset of the disease. For IL-1, IL-5 and IL-10, a significantly rising gradient of levels were observed from healthy to NEC1 to NEC2/3. ConclusionsDifferences in certain faecal cytokine profiles in patients with NEC indicate their potential use as diagnostic biomarkers to facilitate earlier diagnosis. Additionally, associations between microbial and cytokine profiles, contribute to improving knowledge about NEC pathogenesis.

BackgroundAnorectal malformations (ARMs) are rare birth defects with established maternal risk factors. However, the molecular mechanisms linking these risk factors to ARM development remain unclear. Maternal vascular dysfunction may serve as a unifying mechanistic pathway. ObjectiveTo investigate whether mothers of ARM-affected children exhibit molecular signatures of vascular dysfunction using integrated microbiome and metabolomic profiling. MethodsMothers of ARM children (cases; n = 10) and matched healthy controls (n = 10), recruited more than one year postpartum, were analyzed using 16S rRNA sequencing and untargeted LC-MS-based serum metabolomics. Microbial diversity was assessed using Shannon and Chao1 indices; compositional differences were evaluated by PERMANOVA across multiple distance metrics. Metabolites were analyzed using univariate and multivariate methods with FDR correction (q < 0.05). ResultsCases exhibited elevated Firmicutes:Bacteroidetes ratios (70.1% vs 51.6%) and significant depletion of Olsenella (6.2% vs 16.4%, p < 0.05), a genus associated with cortisol metabolism. Metabolomic profiling revealed 174 significantly altered serum metabolites (p < 0.05, fold change >1.5). Among these, reduced D-glutamic acid, elevated thromboxane A , and decreased hexacosanoic acid emerged as key discriminants, mapping to pathways involved in oxidative stress, vasoconstriction, and peroxisomal dysfunction. ConclusionsThis pilot study reveals maternal microbiome-metabolome signatures suggestive of subclinical vascular dysfunction, resembling aspects of pre-eclampsia, in mothers of children with ARMs. These findings support the hypothesis that maternal vascular health influences ARM risk and warrant validation in larger, prospective cohorts. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/25330492v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@11d2066org.highwire.dtl.DTLVardef@13a1778org.highwire.dtl.DTLVardef@dafa2corg.highwire.dtl.DTLVardef@5e9db7_HPS_FORMAT_FIGEXP M_FIG C_FIG

Perinatal transmission of COVID-19 is poorly understood and many neonatal intensive care units (NICU) policies minimize mother-infant contact to prevent transmission. We present our units approach and ways it may impact neonatal microbiome acquisition. We attended COVID-19 positive mothers deliveries from March-August 2020. Delayed cord clamping and skin-to-skin were avoided and infants were admitted to the NICU. No parents visits were allowed and discharge was arranged with COVID-19 negative family members. Maternal breast milk was restricted in the NICU. All twenty-one infants tested negative at 24 and 48 hours and had average hospital stays of nine days. 40% of mothers expressed breastmilk and 60% of infants were discharged with COVID-19 negative caregivers. Extended hospital stays, no skin-to-skin contact, limited maternal milk use, and discharge to caregivers outside primary residences, potentially affect the neonatal microbiome. Future studies are warranted to explore how ours and other centers similar policies influence this outcome.

BackgroundNecrotizing enterocolitis (NEC) is a severe intestinal disease that primarily impacts preterm infants. Current diagnostic tools are inadequate, so urine proteomics was performed for patients with and without NEC to identify putative biomarkers. Research design and methodsThe abundance of urinary proteins detected using an aptamer-based microarray was compared for infants with NEC (n=20) and controls, age-matched (n=8) or self-matched (n=12). Spearman r correlation and hierarchical cluster analysis were performed. The area under the curve (AUC) was calculated for receiver operator characteristic curves (ROC). ResultsNinety-nine proteins differed in NEC vs. controls based on median fold change (Log2 {+/-} 1.1) and significance (P < 0.05). Patterns of abundance were consistent for both types of matching, and samples clustered based on NEC severity. Two panels were built to differentiate between infants with and without NEC. Panel 1 included proteins associated with inflammation/NEC and produced by the intestinal epithelium (REG1B, REG3A, FABP2, DEFA5, AUC 0.90). Panel 2 consisted of proteins with the largest fold change between NEC vs. controls and the highest individual AUC values (REG1B, SSBP1, CRYZL1, ITM2B, IL36B, IL36RN, AUC 0.98). ConclusionsUrine proteins significantly differ between infants with and without NEC, which supports their potential as future biomarkers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/24304374v1_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@415ea9org.highwire.dtl.DTLVardef@1add162org.highwire.dtl.DTLVardef@8d8c41org.highwire.dtl.DTLVardef@f31b62_HPS_FORMAT_FIGEXP M_FIG Graphical abstract. Overview of study findings. Created with Biorender.com C_FIG

IntroductionBronchopulmonary dysplasia (BPD) remains a major complication among extremely low gestational age (ELGA) infants, with long-term respiratory and neurodevelopmental consequences. Despite advances in neonatal care, effective therapies to prevent BPD are lacking. Mesenchymal stromal cells (MSC), particularly those derived from umbilical cord (UC-MSC), offer promise due to their pleiotropic effects. Preclinical and early-phase clinical studies have demonstrated safety and potential efficacy of MSC in neonatal lung injury. The HULC-2 trial aims to evaluate whether multiple intravenous doses of human allogenic UC-MSC can reduce mechanical ventilation duration and improve the respiratory outcome in ELGA infants at high risk of developing BPD. Methods and AnalysisHULC-2 is a multicenter, double-blind, randomized controlled Phase II trial conducted in Canadian Neonatal Intensive Care Units. ELGA infants (gestational age <28 weeks) who remain ventilator-dependent between 4-14 days of life will be randomized to receive either three weekly intravenous doses of UC-MSC (10x10^6 cells/kg/dose) or a sham procedure. The primary outcome is ventilation-free days (VFDs) at 120 days post-randomization, accounting for mortality. Secondary outcomes include cell administration safety, respiratory and neurodevelopmental outcomes, and complications of prematurity. A total of 168 participants will be enrolled to detect a clinically meaningful difference in VFDs. Ethics and DisseminationEthics approval has been obtained, and the trial is registered on ClinicalTrials.gov. Results will be disseminated via peer-reviewed publications, conferences, and public engagement platforms. Parent partners are actively involved in study design and dissemination to ensure relevance and transparency. Strengths and limitations of this studyO_LIVentilation-free day (VFD) is a clinically relevant primary outcome compared to BPD, as prolonged mechanical ventilation in preterm infants is directly associated with increased risks of mortality, neurodevelopmental impairment, and other complications, making VFDs a more sensitive and meaningful measure of both survival and recovery C_LIO_LIUse of a multiple-dose regimen and fresh cell product to optimize the cells therapeutic potential C_LIO_LICell product was tested in a large animal model of BPD C_LIO_LIParents involvement in the trial design and development to deliver meaningful research that benefits patients and increase study acceptance among parents. C_LIO_LIA sham procedure was chosen over a placebo based on parent feedback, which increased the risk of unblinding, but strategies to mitigate that risk were developed. C_LI

Objective(s)To determine the causal relationship between exposure to early hyperoxaemia and death/disability in infants with hypoxic-ischemic encephalopathy (HIE). Study designWe analyzed data from the Infant Cooling Evaluation (ICE) trial that enrolled newborns [&ge;]35 weeks gestation with moderate-severe HIE, randomly allocated to hypothermia or normothermia. The primary outcome was death or major sensorineural disability at 2 years. We included infants with arterial pO2 measured within 2 h of birth. Using a directed acyclic graph, we established that markers of severity of perinatal hypoxia-ischemia and pCO2 were a minimally sufficient set of variables for adjustment in a regression model to estimate the causal relationship between arterial pO2 and death/disability. ResultsAmong 221 infants, 116 (56%) had arterial pO2 and primary outcome data. The unadjusted analysis revealed a U-shaped relationship between arterial pO2 and death/disability. Among hyperoxaemic infants (pO2 100-500 mmHg) the risk of death/disability was 40/58 (0.69), while the risk in normoxaemic infants (pO2 40 - 99mmHg) was 20/48 (0.42). In the adjusted model, hyperoxaemia increased the risk of death/disability (adjusted risk ratio 1.61, 95% CI 1.07 - 2.00, p= 0.03) in relation to normoxaemia. ConclusionsEarly hyperoxaemia increased the risk of death/disability among infants who had an early arterial pO2 in the ICE trial. Limitations include the possibility of residual confounding and other causal biases. Further work is warranted to confirm this relationship in the era of routine therapeutic hypothermia.

Background and ObjectivesCurrent potassium reference intervals for neonates fail to account for sampling method differences and prematurity-related factors, leading to unnecessary resampling and interventions. We aimed to establish sampling-specific potassium reference intervals for term and preterm neonates using comprehensive electronic health record data. MethodsWe analyzed 195 606 blood gas measurements from 10 290 neonates (2007-2024) at a tertiary neonatal intensive care unit. After ex-cluding values during severely impaired clinical conditions using integrated clinical metadata, we derived reference intervals for venous, arterial, and cap-illary samples. Multivariate analysis identified factors affecting potassium homeostasis. ResultsFrom 55 664 included values, capillary samples showed signif-icantly higher potassium levels than arterial or venous samples. Reference intervals (2.5th-97.5th percentiles) for neonates >7 days: venous [2.6, 5.5] mM, arterial [2.6, 5.9] mM, capillary [3.0, 6.3] mM. Time-matched analysis of 5403 paired samples showed capillary-specific intervals achieved 88% sensitivity and 94% specificity for detecting true hyperkalemia compared to arterial or venous controls. ConclusionCapillary blood gas potassium levels require distinct, higher reference intervals than venous or arterial samples in neonates. Implementa-tion of sampling-specific reference ranges may reduce false-positive results and unnecessary interventions in this vulnerable population. Article SummaryLarge EHR-based study defines sampling-specific neonatal potassium reference intervals; higher capillary ranges reduce false positives and maybe unnecessary interventions. Whats Known on This SubjectExisting neonatal potassium reference intervals often ignore sampling modality and prematurity, contributing to clinical uncertainty and unnecessary repeat testing in neonates. What This Study AddsProvides sampling-specific potassium reference intervals for neonates; capillary samples require distinct, higher ranges, improving discrimination of true hyperkalemia and reducing false positives. Contributors Statement PageRudolf G. Ascherl: Conceptualized and designed the study, coordinated data extraction, perfomed analysis and visualization, drafted and revised the initial manuscript. Benjamin W. Ackermann: Contributed to study design, assisted in revising the manuscript. Matthias Knupfer: Provided clinical oversight, interpreted findings, critically reviewed the manuscript. Equal contribution: Rudolf G. Ascherl and Benjamin W. Ackermann. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

ObjectivesTo investigate the impact of early life experiences and gut microbiota on neurobehavioral development among preterm infants during neonatal intensive care unit (NICU) hospitalization. MethodsPreterm infants were followed from the NICU admission until their 28th postnatal day or until discharge. Daily stool samples, painful/stressful experiences, feeding patterns, and other clinical and demographic data were collected. Gut microbiota was profiled using 16S rRNA sequencing, and operational taxonomic units (OTUs) were selected to predict the neurobehaviors. The neurobehavioral development was assessed by the Neonatal Neurobehavioral Scale (NNNS) at 36 to 38 weeks of post-menstrual age (PMA). Fifty-five infants who had NNNS measurements were included in the sparse log-contrast regression analysis. ResultsPreterm infants who experienced high level of pain/stress during the NICU hospitalization that were associated with higher NNNS stress/abstinence scores. Eight operational taxonomic units (OTUs) were identified to be associated with of NNNS subscales after controlling demographic and clinical features, feeding patterns, and painful/stressful experiences. These OTUs, taxa belong to seven genera including Enterobacteriaceae_unclassified, Escherichia-Shigella, Incertae_Sedis, Veillonella, Enterococcus, Clostridium_sensu_stricto_1, and Streptococcus with five belonging to Firmicutes and two belonging to Proteobacteria phylum. The enriched abundance of Enterobacteriaceae_unclassified (OTU17) and Streptococcus (OTU28) were consistently associated with less optimal neurobehavioral outcomes. The other six OTUs were also associated with infant neurobehavioral responses depending on days at NICU stay. ConclusionsThis study explored the dynamic impact of specific OTUs on neurobehavioral development among preterm infants after controlling for early life experiences, i.e., acute and chronic pain/stress, and feeding in the NICU.

BackgroundIn neonates with hypoxic-ischemic encephalopathy (HIE), early biomarkers are needed to enhance prognostic accuracy. We hypothesized that blood lactate kinetics correlate with magnetic resonance imaging (MRI)-based brain injury severity. MethodsIn this prospective cohort study, neonates with HIE admitted to a tertiary neonatal intensive care unit underwent brain MRI within the first week of life. Injury severity was graded using a validated MRI scoring system, with neonates categorized into low severity (LS) or high severity (HS) groups based on the 75th percentile of the total score. Lactate kinetics were evaluated through peak lactate levels, time to lactate normalization (TLN), and area under the curve (AUC). Associations between lactate kinetics and MRI scores were analyzed. ResultsAmong forty-eight neonates, 83% underwent therapeutic hypothermia. Compared with the LS group, the HS group had more seizures, higher Thompson and Sarnat scores, and more abnormal neurological exams at discharge. Peak lactate was higher in the HS group (p=0.02) and correlated with MRI grey matter subscores (p=0.004). Lactate AUC and TLN were positively associated with MRI total and grey matter scores (all p<0.01). ConclusionLactate kinetics are associated with MRI-assessed brain injury severity in HIE and may help stratification to tailor therapeutic strategies. ImpactO_LIBlood lactate kinetics are associated with MRI-assessed brain injury severity in neonates with HIE. C_LIO_LIThis study highlights the value of serial lactate measures, beyond single time-point levels, in early prognostication. C_LIO_LICombining biochemical markers with imaging scores may improve the identification of infants at high risk of adverse outcomes. C_LIO_LIThese findings support the potential use of lactate kinetics to stratify patients and guide future therapeutic strategies. C_LI

BackgroundInhaled nitric oxide (iNO) is a standard treatment for neonatal pulmonary hypertension in high-resource settings. Yet, its efficacy and cost-effectiveness in low- and middle-income countries (LMICs) remain underexplored. This study aimed to evaluate the impact of iNO on neonatal outcomes within a resource-limited Neonatal Intensive Care Unit (NICU) setting in Manaus, Brazil, to inform public health strategies. MethodsWe conducted a multicenter, quasi-experimental study employing a historical control design. We compared outcomes in 12 prospective neonates receiving iNO for persistent pulmonary hypertension of the newborn (PPHN) secondary to perinatal asphyxia (March-August 2018) with 12 historical controls (December 2015-December 2016). Participants were at a gestational age of more than 34 weeks with echocardiographic evidence of PPHN. Main outcomes included oxygenation parameters, mortality, and length of hospital stay. ResultsThe prospective group demonstrated significant acute improvement in all key oxygenation parameters following initiation of iNO (p < 0.01 for PO2, O2 saturation, PO2/FiO2, and Oxygenation Index). However, iNO did not significantly reduce overall mortality (16.6% vs. 0%, p = 0.48) or NICU length of stay (21.3 vs. 13.2 days, p = 0.09). Notably, total hospital length of stay was significantly longer in the iNO group (37.1 vs. 23.08 days, p=0.03), with deaths primarily linked to systemic complications. ConclusionAlthough iNO acutely improves oxygenation in neonates with PPHN in this resource-limited setting, these physiological benefits did not result in reduced mortality or shorter NICU stays and were associated with increased overall hospitalization. The findings indicate that iNO sustains critically ill neonates who subsequently require extended care. Effective implementation of costly interventions in LMICs requires a comprehensive supportive infrastructure. Further context-specific research is crucial for informing resource allocation and enhancing neonatal care.v

ObjectivePulse oximeters overestimate arterial oxygen saturations in black versus white adults, children, and infants. While races impact on near-infrared spectroscopy (NIRS) accuracy is less studied, some adult research suggests decreased accuracy in black patients. This study investigates the effect of race on NIRS accuracy in infants in a cardiac intensive care unit (CICU). Study DesignA retrospective chart review was conducted for infants admitted to St. Louis Childrens Hospital CICU from 2017-2023. Bland-Altman plots, Pearson correlations, and mean biases were analyzed. Result254 infants (13% Black, 87% White) provided 3,687 central venous oxygen saturation (ScvO2)-cerebral regional oxygen saturation (rScO2) pairs. Measurement bias was -3.2% in Black infants and +0.1% in White infants (p<0.01). ConclusionCerebral NIRS underestimates ScvO2 in Black infants but maintains minimal measurement bias in White infants. This is the first study to assess race and NIRS accuracy in infants; the difference is statistically significant but not clinically relevant in most contexts.

Preterm infants are at high risk for systemic inflammatory disorders, including sepsis, meningitis, bronchopulmonary dysplasia, and necrotizing enterocolitis (NEC). The developing brain of the premature newborn is especially susceptible to the cascade of inflammatory mediators elaborated in these conditions that cross the blood-brain barrier. NEC, a severe and potentially fatal condition of the gut that occurs in premature newborns, is a prime example of how an inflammatory reaction, perhaps initially localized, can become generalized and cause systemic harm. One such result is brain injury, especially to the cerebral white matter, which may lead to neurodevelopmental abnormality and dysregulated behavior. Numerous studies have documented an association between necrotizing enterocolitis and neurodevelopmental impairment (NDI), but to date, the brain and behavioral deficits associated with neonatal NEC are not fully understood. We performed a comprehensive systematic review and meta-analysis of existing literature to characterize brain injury and behavioral alterations associated with NEC. 7153 peer-reviewed published manuscripts were screened by two independent reviewers and evidence quality was assessed using GRADE criteria. Of these papers, 62 satisfied the criteria for our review (i.e., no case reports, meta-analyses, systematic reviews, or animal studies). Data from 32 papers using Bayley Scales of Infant and Toddler Development to assess infant outcomes were included in the meta-analysis. Our findings support neonatal necrotizing enterocolitis having deleterious effects on brain and behavioral development and impact on cognitive function, risk of cerebral palsy and motor impairment, educational achievement, behavior, and neuroanatomy. We discuss herein findings of both short-term outcomes (1-3 years) and long-term outcomes (until 13 years). Our meta-analysis also indicates that NEC has a moderate effect size on infant development, with consistent impairment across mental, cognitive, language and motor domains. WHAT DO THE FINDINGS OF THIS REVIEW MEAN?In this review, we describe several short-term and long-term neurodevelopmental outcomes of preterm infants with NEC. These findings suggest that infants with NEC should be monitored with close developmental follow-up so that individuals can receive appropriate testing that may prompt therapies and qualify them to receive early intervention services. HOW UP TO DATE IS THIS REVIEW?The review authors searched for studies published up to 2021. Abstracts with no data available were excluded, so this review does not consider any new findings published from 2022-2024.

ImportancePreterm infants are at high-risk of developing brain injury. Near-infrared spectroscopy (NIRS) offers the ability to measure cerebral oxygenation, potentially reducing brain injury. What remains unknown is the impact of using a standardized treatment guideline combined with a single NIRS device manufacturer and neonatal sensor on cerebral oxygenation, which has not been previously examined. ObjectiveTo determine whether cerebral NIRS monitoring with a dedicated treatment guideline improves cerebral oxygenation stability. DesignThis was a single-blinded, two-arm randomized controlled trial conducted from October 2021 to July 2024. SettingFive tertiary neonatal intensive care units across Australia, New Zealand and the United States. ParticipantsInfants born <29 weeks gestation and <6 hours of age underwent 1:1 random allocation, stratified by gestational age (<26 weeks and [&ge;]26 weeks) and study site. InterventionThe intervention group received cerebral NIRS monitoring and dedicated guideline-based treatment when the cerebral oxygenation was outside the range of 65%-90%. The control group had blinded cerebral NIRS monitoring and treatment guided by standard clinical monitoring. Main Outcome(s) and Measure(s)The burden of cerebral hypoxia and hyperoxia during the first 5 days after birth expressed as percent hours was the primary outcome. Key secondary outcomes were mortality, morbidities before discharge, and NIRS-related skin injury. ResultsOf the 149 screened infants, 100 were included in the final analysis. The median gestational age was 27 weeks (inter quartile range [IQR 25-28]) and the median birth weight was 883 grams (IQR 709-1079). The intervention group (n=50) had a significantly lower median burden of hypoxia and hyperoxia of 5.7% hours (IQR 2.8-15) compared to 39.6% hours (IQR 6.5-82.3) in the standard care group (n=50), with an adjusted reduction of 42.8% hours (95% confidence interval 35.6-53.3, p=0.0002). Mortality, morbidities before discharge and safety outcomes were comparable between groups. Conclusions and RelevanceTreatment guided by cerebral NIRS monitoring with a single device manufacturer and neonatal sensor, is a safe and low-risk intervention that significantly improves stability of cerebral oxygenation in extremely preterm infants. Larger multicenter trials are warranted to determine if this finding leads to improved survival without brain injury. Trial RegistrationThe trial is registered at The Australian New Zealand Clinical Trials Registry, registration number: ACTRN12621000778886, and https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12621000778886 Key pointsO_ST_ABSQuestionC_ST_ABSDoes cerebral near infrared spectroscopy (NIRS) with a dedicated treatment guideline using NIRS device from a single manufacturer and neonatal sensor improve cerebral oxygenation stability in extremely preterm infants? FindingsIn this randomized clinical trial of 100 infants, the burden of cerebral hypoxia and hyperoxia was significantly lower in the intervention group (5.7% hours) compared to standard care group 39.6% hours. MeaningTreatment guided by cerebral NIRS monitoring is a safe and low-risk intervention that improves stability of cerebral oxygenation in extremely preterm infants.

BackgroundApnoea is a common respiratory complication in preterm neonates, leading to substantial changes in physiology. We conducted this systematic review and meta-analysis to examine the relationship between apnoea duration and changes in physiology in preterm neonates, and to identify factors that modulate this relationship. MethodsWe searched Medline, EMBASE, PsycINFO, and Cochrane Central Register of Controlled Trials databases and included primary empirical studies examining the relationship between apnoea or respiratory pause duration and at least one outcome (heart rate, blood oxygen saturation, cerebral oxygenation, cerebral blood volume) in hospitalised neonates with postmenstrual age (PMA) <37 weeks. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal checklist. Results were synthesised narratively and quantitative data was pooled for meta-analysis. ResultsForty-two papers were included, involving a total of 1,483 neonates with 2,399 study sessions. The decrease in heart rate, oxygen saturation, and cerebral oxygenation were significantly correlated with apnoea duration. PMA significantly modulated the relationship, with younger neonates more likely to exhibit oxygen desaturation from short apnoeas. ConclusionsThese findings indicate that shorter apnoea alarm thresholds should be considered for younger infants. Impact statement: What is the key message of your article?O_LISystematic review and meta-analysis of the relationship between change in physiology and apnoea duration in preterm infants. C_LI What does it add to the existing literature?O_LIThrough meta-analysis, we demonstrate that postmenstrual age plays a significant modulating role in the relationship between apnoea duration and change in oxygen saturation, with younger infants more likely to have significant desaturations. C_LI What is the impact?O_LIWe propose that age-stratified apnoea alarm limits are considered to prevent physiological instability in newborns. C_LI